The present invention relates to a novel crystalline form of sertraline hydrochloride, and reproducible methods for its preparation.
Sertraline hydrochloride, (1S-cis)-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula 
is approved, under the trademark Zoloft(copyright), by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. Pat. No. 4,536,518 (xe2x80x9cthe ""518 patentxe2x80x9d) describes the preparation of sertraline hydrochloride with a melting point of 243-245xc2x0 C. by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the sertraline hydrochloride so produced are not otherwise disclosed.
U.S. Pat. No. 5,734,083 describes the preparation of a form of sertraline hydrochloride denominated polymorph xe2x80x9cT1.xe2x80x9d
According to U.S. Pat. No. 5,248,699 (xe2x80x9cthe ""699 patentxe2x80x9d), the sertraline hydrochloride produced by the method of the ""518 patent has a crystalline form denominated xe2x80x9cForm II.xe2x80x9d The ""699 patent discloses four other polymorphs of sertraline hydrochloride designated Forms I, III, IV, and V, and characterizes them by single crystal x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimetry. The ""699 patent reports that Form II is produced by rapid crystallization of sertraline hydrochloride from an organic solvent, including isopropyl alcohol, ethyl acetate or hexane, and generally describes methods for making sertraline hydrochloride Forms I-V. According to this patent, the preferential formation of Forms I, II or IV in an acidic solution consisting of isopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on the rapidity of crystallization. The only method described in this patent for making Forms II and IV is by the rapid crystallization of sertraline hydrochloride from an organic solvent such as those listed above.
The experimental procedure for the preparation of sertraline hydrochloride described in the ""518 patent, was repeated in the laboratory. According to the ""699 patent, the ""518 procedure produces sertraline hydrochloride Form II. Four experiments were performed according to the description in the ""518 patent. By following the procedures described in the ""699 patent for preparation of sertraline hydrochloride Form II, we were unable to obtain sertraline hydrochloride Form II. Thus there remains a need for reproducible methods for the preparation of sertraline hydrochloride Form II.
The present invention relates to a process for making sertraline hydrochloride Form II comprising the steps of dissolving sertraline base or sertraline mandelate in an organic solvent to form a solution; adding hydrogen chloride to the solution; heating the solution to a temperature between about room temperature and about reflux for a time sufficient to induce the formation of sertraline hydrochloride Form II; and isolating sertraline hydrochloride Form II.
The present invention also relates to a process for making sertraline hydrochloride Form II comprising the steps of dissolving sertraline hydrochloride in dimethylformamide, cyclohexanol, acetone or a mixture thereof; heating the solution for a time sufficient to effect transformation to sertraline hydrochloride Form II; and isolating sertraline hydrochloride Form II.
The present invention further relates to a process for making sertraline hydrochloride Form II comprising the steps of granulating sertraline hydrochloride Form V in ethanol or methanol; and stirring the mixture of sertraline hydrochloride Form V and ethanol or methanol for a time sufficient to induce transformation to sertraline hydrochloride Form II.
The present invention still further relates to a process for making a mixture of sertraline hydrochloride Form II and Form V comprising the steps of heating sertraline hydrochloride ethanolate Form VI at up to 1 atmosphere pressure; and isolating a mixture of sertraline hydrochloride Form II and Form V.
The present invention still further relates to a process for making sertraline hydrochloride Form II comprising the steps of suspending a water or solvent adduct of sertraline hydrochloride in a solvent selected from the group consisting of acetone, t-butyl-methyl ether, cyclohexane, n-butanol, and ethyl acetate such that a slurry is formed, for a time sufficient to effect transformation to sertraline hydrochloride Form II; and filtering the slurry to isolate sertraline hydrochloride Form II.
The present invention still further relates to sertraline hydrochloride Form II, characterized by an x-ray powder diffraction pattern comprising peaks at about 5.5, 11.0, 12.5, 13.2, 14.7, 16.4, 17.3, 18.1, 19.1, 20.5, 21.9, 22.8, 23.8, 24.5, 25.9, 27.5, and 28.0 degrees two theta; pharmaceutical compositions for the treatment of depression comprising sertraline hydrochloride Form II together with a pharmaceutically acceptable carrier, and a method for treating depression comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of the such a pharmaceutical composition.